This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. I. HYPOTHESIS Hypothesis 1: A genetic defect is a likely causative factor for biliary atresia (BA) among children with BA and multiple congenital anomalies. Hypothesis 2: Autoimmune factors are likely to contribute to disease progression or acquisition and can be identified by correlating HLA among children with BA to healthy controls and by comparison of those who develop early complications including, variceal bleed, ascites, and growth failure compared to those who do not. Hypothesis 3a: Sentinel events such as variceal bleeding, ascites and growth failure are earlier predictors of death or need for liver transplantation than the pediatric end-stage liver disease score (PELD). Hypothesis 3b: Health related quality of life will be impaired compared to healthy age matched children and relate to severity of illness. Hypothesis 3c: Growth failure as measured by anthropometrics and nutritional supplementation will be predictive of onset of sentinel events (ascites, variceal bleed, death, and transplant) in the following 24 months. II.
SPECIFIC AIMS Little is known about the factors that cause biliary atresia nor the factors that influence disease progression. A variety of genetic, autoimmune and environmental influences have been hypothesized to be important. Most studies to date have focused on the neonate and young child with BA, yet the older surviving child with BA can provide important information about genetics, as well as, natural history. The purpose of this database is to collect the pertinent clinical information, genetic material and body fluid samples to enable investigators to address the above hypotheses and the following related aims:
Specific Aim 1. To identify the gene or genes implicated in the etiology of BA Specific Aim 2. To identify polymorphisms that may be important in disease progression such as HLA polymorphisms i.To perform high resolution HLA-A, B, C, DRB1, DRB3 DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1 typing on patients with biliary atresia. ii.To utilize a novel computer algorithm that permits screening large numbers of HLA alleles to detect shared epitopes in patients with biliary atresia. iii.To assess the role of HLA polymorphism in incidence and severity of biliary atresia using traditional analysis of allele frequency and a novel shared epitope algorithm.
Specific Aim 3. Characterize the natural history of the older, non-transplanted child with BA. III. BACKGROUND AND SIGNIFICANCE Extrahepatic biliary atresia (BA) is a devastating condition of infancy in which there is obliteration or discontinuity of the hepatic or common bile ducts at any point from the porta hepatitis to the duodenum. When untreated, the condition results in severe liver injury and death in all cases. The development of the hepatoportoenterostomy procedure in 1959 by Kasai has permitted long-term survival in only 20% of the affected infants. The advent of liver replacement therapy has permitted long-term survival in many of the remaining infants, but not without cost and morbidity. The estimated incidence of BA is 1 in 8,000 to 1 in 18,000 live births. Approximately 50 percent of all liver transplantations in children in the United States are for infants with BA-constituting 140-180 liver transplants per year. Despite the devastating nature of this illness and the high cost of its treatment, we still know very little about its pathogenesis nor the factors implicated in disease progression. It is likely that BA is not a single disease, but rather a phenotype of several underlying specific disorders to which the infant liver responds in a stereotypic manner by a complex series of processes, including inflammation, bile duct proliferation, apoptosis and fibrogenesis. Improvement in outcomes will not occur until we have a better understanding of the mechanisms involved in these processes.
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